[The value of re-evaluation and thorough family history taking for the diagnostic work-up of chorea]. / Het diagnostisch proces bij chorea: het belang van heroverwegen en de familieanamnese.

The differential diagnosis of chorea encompasses a broad range of disorders. In psychiatry, tardive dyskinesia may be difficult to discern from other causes, particularly when the family history is negative. A 59-year-old man with an unclear medical history had been using risperidone for over a decade when we first saw him. He presented with severe dyskinesia in all extremities. The family history for neuropsychiatric disorders was negative. We interpreted the movement disorder as tardive dyskinesia, but later he turned out to suffer from Huntington’s disease. To improve diagnostic accuracy, we should have more frequently re-evaluated the differential diagnosis and our family history should have been more thorough. We outline the diagnostic considerations in patients presenting with chorea. Finally, we highlight the value of diagnostic re-evaluation and thorough family history taking to optimize diagnostic accuracy in neuropsychiatry.

An interexaminer agreement and reliability study on cadavers with musculoskeletal ultrasound of the shoulder performed by physiotherapists and radiologists compared with dissection.

STUDY DESIGN: A cross-sectional inter-examiner agreement and reliability study on fresh frozen cadaver shoulders. BACKGROUND: Musculoskeletal ultrasound (MSU) is frequently used by physical therapists and radiologists to improve specific diagnosis in rotator cuff related pathology. The evaluation of the rotator cable seems to be important as stabilizing structure when cuff tears occur. OBJECTIVES: To evaluate the inter-examiner agreement and reliability of MSU of the shoulder to detect rotator cuff-pathology and the involvement of the rotator cable in comparison to "dissection". METHODS: Physical therapists, a radiologist and an orthopedic surgeon (dissection) investigated 40 fresh frozen cadaver shoulders in order to detect shoulder pathology including rotator cable involvement. Examiners were blinded to each other's findings. RESULTS: We found a strong and significant agreement between the raters: PTs, the radiologist and the dissector in this cadaver study for all rotator cuff, the long head of the biceps pathologies and in detecting abnormalities of the rotator cable. The kappa value was substantial to (almost) perfect agreement for all diagnostic outcome categories. CONCLUSIONS: This study shows that among a limited group of physical therapists, one radiologist and a dissector a strong level of agreement with kappa values from substantial to (almost) perfect in finding subacromial pathology.

Diagnostic ultrasound in patients with shoulder pain: An inter-examiner agreement and reliability study among Dutch physical therapists.

STUDY DESIGN: A cross-sectional inter-examiner agreement and reliability study among physical therapists in primary care. BACKGROUND: musculoskeletal ultrasound (MSU) is frequently used by physical therapists to improve specific diagnosis in patients with shoulder pain, especially for the diagnosis rotator cuff tendinopathy (RCT) including tears. OBJECTIVES: To estimate the inter-examiner agreement and reliability in physical therapists using MSU for patients with shoulder pain. METHODS: Physical therapists performed diagnostic MSU in 62 patients with shoulder pain. Both physical therapists were blinded to each other's results and patients were not informed about the test results. We calculated the overall inter-examiner agreement, specific positive and negative inter-examiner agreement, and inter-examiner reliability (Cohen's Kappa's). RESULTS: Overall agreement for detecting RC ruptures ranged from 61.7% to 85.5% and from 43.9% to 91.4% for specific positive agreement. The specific negative agreement was lower with values ranging from 44.4% to 79.1% for RC ruptures. Overall agreement for other pathology than ruptures related to SAPS, ranged from 72.6% to 93.6% and from 77.3% to 96% for specific positive agreement. The specific negative agreement was lower with values ranging from 44.4% to 79.1% for RC ruptures and 52.5%-83.3% for other pathology than ruptures related to SAPS. Reliability values varied from substantial for any thickness ruptures to moderate for partial thickness ruptures and fair for full thickness tears. Moreover, reliability was fair for cuff tendinopathy. The reliability for AC arthritis and no pathology found was fair and moderate. There was substantial agreement for the calcifying tendinopathy. CONCLUSIONS: Physical therapists using MSU agree on the diagnosis of cuff tendinopathy and on the presence of RCT in primary care, but agree less on the absence of pathology.

Agreement between physical therapists and radiologists of stratifying patients with shoulder pain into new treatment related categories using ultrasound; an exploratory study.

STUDY DESIGN: A systematic overview of the literature and an agreement study. OBJECTIVES: The aim of this study is to explore the inter-professional agreement of diagnostic musculoskeletal ultrasound (DMUS) between physical therapists (PT) and radiologists, using a new classification strategy based upon the therapeutic consequences in patients with shoulder pain. BACKGROUND: DMUS is frequently used by PTs, although the agreement regarding traditional diagnostic labels between PTs and radiologists is only fair. Nevertheless, DMUS could be useful when used as a stratifying-tool. METHODS: First, a systematic overview of current evidence was performed to assess which traditional diagnostic labels could be recoded into new treatment related categories (referral to secondary care, corticosteroid injections, physical therapy, watchful waiting). Next, kappa values were calculated for these categories between PTs and radiologists. RESULTS: Only three categories were extracted, as none of the traditional diagnostic labels were classified into the 'corticosteroid injection' category. Overall, we found moderate agreement to stratify patients into treatment related categories and substantial agreement for the category 'referral to secondary care'. Both categories 'watchful waiting' and 'indication for physical therapy' showed moderate agreement between the two professions. CONCLUSION: Our results indicate that the agreement between radiologists and PTs is moderate to substantial when labelling is based on treatment consequences. DMUS might be able to help the PT to guide treatment, especially for the category 'referral to secondary care' as this showed the highest agreement. However, as this is just an explorative study, more research is needed, to validate and assess the consequences of this stratification classification for clinical care.

Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis.

AIMS: Several authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations. METHODS: A meta-analysis of cohort and case-control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up. RESULTS: The risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43-3.87) in affective disorder populations to 8.00 (95% CI 5.46-11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74-2.64) than in non-psychiatric participants (risk 0.23%, 95% CI 0.10-0.54). Past suicide attempt-adjusted risk ratios were not pooled due to large underreporting. CONCLUSIONS: Assessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide.

Physiotherapy for patients with shoulder pain in primary care: a descriptive study of diagnostic- and therapeutic management.

BACKGROUND: Shoulder pain is one of the three main musculoskeletal complaints and more than 50% of the patients have symptoms longer than 6 months. Until now, limited data exist about the content of physiotherapy for patients with shoulder pain in primary care. OBJECTIVE: Describe current physiotherapeutic diagnostic- and therapeutic management, including the use of diagnostic ultrasound, in patients with shoulder pain in primary care. DESIGN AND SETTING: A prospective cohort study in primary care physiotherapy with a 12 week follow-up. METHODS: Descriptive data from physiotherapists was collected, such as: the diagnostic hypotheses after patient history and physical examination, the use of specific tests and diagnostic ultrasound, the interventions used and possible changes in treatment plan. RESULTS: Subacromial impingement syndrome was the most common hypothesis after patient history (48%) as well as physical examination (39%). Diagnostic ultrasound was used in 31% and of these patients the clinical diagnosis changed in 29%. Various interventions were used in all clinical diagnoses. After 12 weeks 41% of patients still received physiotherapy treatment. CONCLUSIONS: Patients with shoulder pain in physiotherapy practice frequently show signs of subacromial impingement syndrome. The interventions used by the physiotherapists were generally in line with the guideline for subacromial impingement syndrome however a small proportion of physiotherapists used massage and tape/bracing techniques. A large proportion of patients were still receiving treatment after 12 weeks when no improvement was observed. If treatment for patients with subacromial impingement shows no benefit patients should be referred back to the general practitioner or orthopedic surgeon. Conclusions from this study might be slightly biased because of the selection of physiotherapists.

[Delayed diagnosis of Huntington's disease in a psychiatric setting]. / Vertraagde diagnose van de ziekte van Huntington in een psychiatrische setting.

Huntington's disease (hd) is characterised by a triad of neuropsychiatric symptoms, motor disturbances and cognitive decline. If initial symptoms are of neuropsychiatric nature they maybe misinterpreted, which can lead to delayed diagnosis. Three examples of delayed hd diagnosis in a psychiatric setting are discussed.

Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages.

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 µg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease and its association with depressive symptoms and suicidality.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi ) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early and advanced disease stages, ß values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study.

Inter-professional agreement of ultrasound-based diagnoses in patients with shoulder pain between physical therapists and radiologists in the Netherlands.

STUDY DESIGN: Reliability study. OBJECTIVES: The aim of this study was to evaluate the interrater-reliability of the interpretation of diagnostic ultrasound in patients with shoulder pain between physical therapists and radiologists. BACKGROUND: Although physical therapists in The Netherlands increasingly use diagnostic ultrasound in clinical practice, there is no evidence available on its reliability. METHODS: A cohort study included patients with shoulder pain from primary care physiotherapy. Patients followed the usual diagnostic pathway of which diagnostic ultrasound could be a part. Patients that received diagnostic ultrasound also visited a radiologist within one week for a second one. Patients and radiologists were blinded for the diagnostic ultrasound diagnosis of the physical therapists. Agreement was assessed using Cohen's kappa statistics. Subgroup analysis was performed on education and experience. RESULTS: A total of 65 patients were enrolled and 13 physical therapists and 9 radiologists performed diagnostic ultrasound. We found substantial agreement (0.63 K) between physical therapists and radiologists on the assessment of full thickness tears. The overall kappa of all four diagnostic categories was 0.36, indicating fair agreement. The more experienced and highly trained physical therapists showed moderate agreement (0.43 K) compared to only slight agreement (0.17 and 0.09 K) from the less experienced and trained physical therapists with radiologists. CONCLUSION: The reliability between physical therapists and radiologist on diagnostic ultrasound of shoulder patients in primary care is borderline substantial (Kappa = 0.63) for full thickness tears only. This level of reliability is relatively low when compared with the high reliability between radiologists. More experience and training of physical therapists may increase the reliability of diagnostic ultrasound.

Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington's disease.

Activation of the innate immune system has been postulated in the pathogenesis of Huntington's disease (HD). We studied serum concentrations of C-reactive protein (CRP) and low albumin as positive and negative acute-phase proteins in HD. Multivariate linear and logistic regression was used to study the association between acute-phase protein levels in relation to clinical, neuropsychiatric, cognitive, and psychotropic use characteristics in a cohort consisting of 122 HD mutation carriers and 42 controls at first biomarker measurement, and 85 HD mutation carriers and 32 controls at second biomarker measurement. Significant associations were found between acute-phase protein levels and Total Functioning Capacity (TFC) score, severity of apathy, cognitive impairment, and the use of antipsychotics. Interestingly, all significant results with neuropsychiatric symptoms disappeared after additional adjusting for antipsychotic use. High sensitivity CRP levels were highest and albumin levels were lowest in mutation carriers who continuously used antipsychotics during follow-up versus those that had never used antipsychotics (mean difference for CRP 1.4 SE mg/L; P=0.04; mean difference for albumin 3 SE g/L; P<0.001). The associations found between acute-phase proteins and TFC score, apathy, and cognitive impairment could mainly be attributed to the use of antipsychotics. This study provides evidence that HD mutation carriers who use antipsychotics are prone to develop an acute-phase response.

Psychiatric disorders in Huntington's disease: a 2-year follow-up study.

OBJECTIVE: This study investigates the presence and course of formal psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) in 142 Huntington's disease (HD) mutation carriers in a two-year follow-up design. METHOD: Of the 142 mutation carriers, 106 (75%) participated in the second measurement of an ongoing cohort study on psychopathology in HD. Presence of psychiatric disorders was assessed using the Composite International Diagnostic Interview. RESULTS: Of the 91 patients without a formal psychiatric disorder at baseline, 14 (15%) had a psychiatric disorder after 2 years, mostly a major depressive disorder (MDD) (64%). The baseline characteristics of lower education, having no children, a lower level of global daily functioning, a lifetime psychiatric diagnosis, and the use of psychotropic medication were predictive of incident psychiatric disorders after 2 years. Of the 15 patients with a psychiatric diagnosis at baseline, eight (53%) no longer had a psychiatric disorder at follow-up. All seven patients (47%) with a persistent psychiatric disorder were female and their most prevalent diagnosis was generalized anxiety disorder. CONCLUSION: This cohort study confirms that psychiatric disorders, in particular MDD, frequently occur in patients with HD. Professionals working with HD patients should therefore be aware of the high risk of psychopathology in HD because early diagnosis and treatment of psychiatric disorders may improve the quality of life of patients and their caregivers.

Suicidality in Huntington's disease.

BACKGROUND: In Huntington's disease (HD) the risk of suicide is increased. Since suicidality may precede suicide, this study investigates prevalence, clinical associations and predictors of suicidality in HD. METHODS: Suicidality was investigated in 152 mutation carriers and 56 non-carriers, and was considered present if the score on the item 'suicidal ideation' of the Problem Behaviours Assessment (PBA) was >1 point. After 2 years, 100 mutation carriers who were free of suicidality at baseline were re-assessed. Associations and predictors of suicidality were analyzed using multivariate logistic regression analysis. RESULTS: Eleven (20%) pre-motor and 20 (20%) motor symptomatic mutation carriers were considered suicidal compared to none of the non-carriers. Cross-sectionally, suicidal mutation carriers were more likely to use antidepressants (odds ratio=5.3), were more often apathetic (OR=2.8), more often had a depressed mood according to the PBA (OR=5.9), and were more often diagnosed with a DSM-IV depression diagnosis (OR=4.7). Independent associations were more frequent use of antidepressants (OR=4.0) and presence of a depressed mood (OR=4.2). Longitudinally, depressed mood (OR=10.6) at baseline was the only independent predictor of suicidality at follow-up. LIMITATIONS: Selection bias might have occurred which could have affected the suicidality rate. CONCLUSION: It is important to screen both pre-motor and motor symptomatic HD mutation carriers for suicidality. The presence of a depressed mood is both associated with and predictive of suicidality in HD and assessment of depressed mood can help to identify individuals with increased risk for suicide.

Adverse childhood experiences of persons at risk for Huntington's disease or BRCA1/2 hereditary breast/ovarian cancer.

Huntington's disease (HD) is known to have a negative impact on family life. Offspring of HD patients may be exposed to adversity in childhood because of the parent's disease and its psychological consequences. BRCA1/2 hereditary breast and ovarian cancer (BRCA1/2) increases the risk for offspring of being exposed to parental disease or loss. Childhood adversity is associated with psychopathology and various other problems in later life. Adverse childhood experiences (ACEs) before age 16 were assessed in adults at 50% risk for HD (n = 74) or BRCA1/2 (n = 82) and in controls (n = 101), using the Negative Life Events Scale. Mean number and occurrence of ACEs were compared between groups. The odds of having experienced adversity in childhood were higher in HD offspring and BRCA1/2 offspring than in controls. HD offspring reported a higher mean number of ACEs than controls or BRCA1/2 offspring. In HD offspring, the prevalence of parental disease and parental dysfunction experienced before age 16 was higher than in controls. In BRCA1/2 offspring, the prevalence of parental loss before age 16 was higher than in controls. This study indicates that 53% of HD offspring and 45% of BRCA1/2 offspring are exposed to adversity in childhood or adolescence. The relevance of these findings for counseling in predictive testing programs, reproductive decision-making, and child rearing matters is discussed.

Correlates of apathy in Huntington's disease.

The authors aim to study prevalence and clinical correlates of apathy in Huntington's disease. Apathy was defined as an Apathy Scale score > or =14 points in 152 Huntington's disease mutation carriers and 56 noncarriers. Correlates of apathy were analyzed cross-sectionally in mutation carriers using multivariable logistic regression analysis. Forty-nine (32%) Huntington's disease mutation carriers showed apathy compared to none of the noncarriers. After exclusion of 10 depressed patients, apathy was independently associated with male sex, worse global functioning, and higher use of neuroleptics and benzodiazepines.

Psychopathology in verified Huntington's disease gene carriers.

Huntington's disease is characterized by motor, cognitive, and neuropsychiatric symptoms. This study reviews original research on psychopathology in Huntington's disease that uses standardized instruments in verified gene carriers. Frequently reported neuropsychiatric symptoms are depressed mood, anxiety, irritability, and apathy, with prevalences of 33% to 76%. Obsessive-compulsive symptoms and psychosis occur less often with prevalences of 10% to 52% and 3% to 11%, respectively. Available research provides little insight into the true prevalences of psychopathology in Huntington's disease due to small sample sizes, use of different methodologies, and lack of comparison groups. Future research requires larger cohorts stratified to disease stage, consistent methodologies, and adequate comparison groups.

A narrow-band injection-seeded pulsed titanium:sapphire oscillator-amplifier system with on-line chirp analysis for high-resolution spectroscopy.

A narrow-band tunable injection-seeded pulsed titanium:sapphire laser system has been developed for application in high-resolution spectroscopic studies at the fundamental wavelengths in the near infrared as well as in the ultraviolet, deep ultraviolet, and extreme ultraviolet after upconversion. Special focus is on the quantitative assessment of the frequency characteristics of the oscillator-amplifier system on a pulse-to-pulse basis. Frequency offsets between continuous-wave seed light and the pulsed output are measured as well as linear chirps attributed mainly to mode pulling effects in the oscillator cavity. Operational conditions of the laser are found in which these offset and chirp effects are minimal. Absolute frequency calibration at the megahertz level of accuracy is demonstrated on various atomic and molecular resonance lines.

[Electroconvulsive therapy in patients with Huntington's disease and depression]. / Elektroconvulsietherapie bij patiënten met de ziekte van Huntington en depressie.

Two patients, a 50-year-old man and a 51-year-old woman, with genetically confirmed Huntington's disease (HD) were admitted to a psychiatric department because of therapy-resistant major depression. Both patients were successfully treated with electroconvulsive therapy (ECT). The lifetime prevalence of depression in HD patients is high and, together with movement and cognitive disturbances, causes a heavy disease burden for patients and their families. ECT is an effective and relatively fast antidepressive treatment. Although ECT use has been reported in only 11 depressive HD patients in the literature, in our opinion it is an adequate antidepressive treatment that should be considered before further drug treatment for patients who are substantially limited in their daily functioning.

Production of narrowband tunable extreme-ultraviolet radiation by noncollinear resonance-enhanced four-wave mixing.

Fourier-transform-limited extreme-ultraviolet (XUV) radiation (bandwidth approximately < 300 MHz) tunable around 91 nm is produced by use of two-photon resonance-enhanced four-wave mixing on the Kr resonance at 94 093 cm(-1). Noncollinear phase matching ensures the generation of an XUV sum frequency 2 omega1 + omega2 that can be filtered from auxiliary laser beams and harmonics by an adjustable slit. Application of the generated XUV light is demonstrated in spectroscopic investigations of highly excited states in H2 and N2.